Scripps Research Institute has received a USD 1.62 million NIAID R01 grant to advance preclinical development of two novel small-molecule inhibitors targeting the polymerase and endonuclease activities of the mammarenavirus L protein — enzymes essential for viral replication that currently lack approved therapeutic agents.
The grant supports efforts to develop antiviral therapies for mammarenaviruses, a longstanding gap in hemorrhagic fever preparedness. Lassa virus, endemic across West Africa, and Junin virus, circulating in Argentina's Pampas region, cause viral hemorrhagic fevers with significant mortality and no FDA-licensed vaccines or approved antivirals. Ribavirin, the only available treatment, is used off-label with disputed efficacy. Both pathogens are classified as Category A biodefense agents. Lymphocytic choriomeningitis virus, though globally distributed and less recognized clinically, poses serious risk to immunocompromised individuals and neonates.
Principal investigator Juan C. de la Torre and colleagues at the La Jolla, California nonprofit research institute have identified two lead compounds — mCOT466, which inhibits the viral RNA-dependent RNA polymerase, and mCPB916, which targets the cap-snatching endonuclease (EndoN) — that demonstrated activity against both Old World (Lassa, LCMV) and New World (Junin) mammarenaviruses. The L protein carries both enzymatic functions, making it an attractive dual target. The five-year project, running through June 2031, will characterize mechanisms of action, resistance profiles, and broad-spectrum activity across hemorrhagic fever-causing mammarenaviruses and related Bunyaviricetes.
Medicinal chemistry and ADMET optimization are planned to develop oral prodrug candidates with suitable pharmacokinetic and pharmacodynamic profiles for IND-enabling studies. In vivo efficacy will be assessed in validated animal models of lethal Lassa and Junin infection, in both monotherapy and combination regimens.
The grant builds on previous work from de la Torre and collaborators characterizing mCOT466 (4′-FlA), a broad-spectrum nucleoside analogue that inhibits viral RNA polymerases across multiple RNA virus families. The newly funded project will evaluate the compound's activity against mammarenaviruses and optimize it for preclinical development.